Despite tremendous advancements in drug delivery oral route remains the preferred route of administration for therapeutic agents because of low cost of therapy and ease of administration leading to high levels of patient compliance. A number of oral delivery systems have been developed which act as drug reservoirs from which the active substance can be released over a defined period of time at a predetermined and controlled rate. Such systems reduce dosage frequency, resulting in increased patient compliance. However, the conventional controlled release drug delivery systems have limited use in instances such as (1) drugs having an absorption window in the gastrointestinal tract; (2) local treatment of proximal parts of the gastrointestinal tract (stomach and/or duodenum); (3) drugs which degrade or are unstable in the intestinal/colonic environment; (4) drugs that exhibit low solubility at high pH values; and (5) drugs requiring a longer duration in the intestine.
All therapeutic agents are not absorbed uniformly throughout the gastrointestinal tract. Some drugs are absorbed from a particular portion of the gastrointestinal tract or are absorbed to a different extent in various segments of gastrointestinal tract. Such active agents are said to have an “absorption window”. Thus, only the drug substance released in the region preceding and in close vicinity of the absorption window is available for absorption. After crossing the absorption window, the released drug substance will show very little or no absorption. This phenomenon drastically limits the success of a delivery system and, therefore, has led to the development of oral controlled release dosage forms exhibiting delayed transit through gastrointestinal tract. Such a dosage form can possess gastrointestinal retention capabilities and can hold these active agents near their absorption window for extended time periods, thereby achieving controlled release and/or improved bioavailability of the active ingredient.
Further, dosage forms with increased gastric residence time are advantageous for local action in the stomach and the upper part of the small intestine, for example treatment of peptic ulcer disease. Further, drugs which degrade or are unstable in the colonic/intestinal environment or exhibit low solubility at high pH values can be delivered to the upper gastrointestinal tract effectively via gastroretentive drug delivery systems. Overall maximized absorption of such therapeutic agents can be achieved by increasing the gastrointestinal retention time of the controlled release dosage form in the gastrointestinal tract, thus providing a constant stream of supply of the therapeutic agent for improved drug bioavailability benefits.
The gastrointestinal retention of solid dosage forms may be achieved by various mechanisms, such as mucoadhesion, flotation, sedimentation, swelling and expansion, or by the simultaneous administration of pharmacological agents which delay gastric emptying. Mucoadhesion relates to adhesion of the polymer utilized in the delivery system to the gastrointestinal mucus layer until it is removed spontaneously from the surface. Various physiological factors such as peristalsis, mucin turnover rate, gastrointestinal pH, fast/fed state and type of foods affect the degree of mucoadhesion. The mechanism of mucoadhesion is thought to be through the formation of electrostatic and hydrogen bonding at the polymer-mucus boundary. Generally, mucoadhesion is achieved with polymers having affinity for gastrointestinal mucosa and selected from a group comprising polycarbophils, carbomers, alginates, chitosan, gums, lectins, cellulose and cellulose derivatives or mixtures thereof.
Floatation as a retention mechanism works in cases wherein the delivery system has a bulk density lower than gastric fluid and remains buoyant in the stomach. These buoyant systems generally utilize matrices prepared with swellable polymers or polysaccharides and effervescent couples, e.g., sodium bicarbonate and citric or tartaric acid or matrices containing chambers of entrapped air or liquids that gasify at body temperature. In case of sedimentation or densification as a mechanism for gastroretention, the dosage form has high bulk density compared to the density of gastric contents. Such systems usually multiparticulates are retained in the rugae or folds of the stomach near the pyloric region and tend to withstand the peristaltic movements of the stomach wall. Further, these high density particles are also shown to significantly prolong the intestinal transit time.
Swelling and expansion is a potentially reliable retention mechanism wherein on swallowing the dosage form swells to an extent that prevents exit from the stomach through the pylorus. As a result, the dosage form is retained in the stomach for a long period of time. These systems are referred as ‘plug type system’ since they exhibit tendency to remain lodged at the pyloric sphincter. These dosage forms are excluded from the passage of the pyloric sphincter as they exceed a diameter of approximately 10-12 mm in their swollen or expanded state. The concept of simultaneous administration of a drug to delay gastric emptying together with a therapeutic active due to unfavorable response from clinicians and regulatory agencies because of the questionable benefit-to-risk ratio associated with their usage have been employed in a limited way.
Many researchers have developed gastroretentive drug delivery systems based on any one or a combination of the above mentioned mechanisms. The specific use of mucoadhesive formulations in the treatment of gastric disorders (including H. pylori) has been described in PCT Publication 92/18143. Prolonged gastric retention and sustained release is achieved by use of bioadhesive materials like natural gums and plant extracts and synthetic materials such as sucralfate, cellulose derivatives, acrylic acid and methacrylic acid derivatives, for example cross-linked acrylic and methacrylic acid copolymers available under the Trade Names CARBOPOL and POLYCARBOPHIL. GB Patent Application 2324725A1 highlights a pharmaceutical composition suitable for forming a mucoadhesive lining in the gastrointestinal tract comprising a particular form of alginic acid or alginate salt characterised in that the mannuronic acid:glucoronic acid residue ratio (M/G) is at least unity and effective to provide a bioadhesive interaction with the mucosa. U.S. Patent Application 20070128276A1 emphasizes a controlled release composition comprising nimesulide as an active agent formulated as a gastroretentive system. Herein mucoadhesion is achieved by treating nimesulide with polymers having affinity for gastrointestinal mucosa selected from a group comprising polycarbophils, carbomers, alginates, cellulose and cellulose derivatives, chitosan, gums, lectins, or mixtures thereof.
Many attempts have also been made to devise extended release gastroretentive drug delivery systems wherein the dosage form is small enough to ingest but is then retained after swelling in the gastro-intestinal area for a long enough time for the active agent to be released and eventually absorbed.
U.S. Patent Application 20030104053A1 discloses unit dosage form tablets for the delivery of pharmaceuticals wherein the active is dispersed in a solid unitary matrix that is formed of a combination of poly (ethylene oxide) and hydroxypropyl methylcellulose. This combination is said to offer unique benefits in terms of release rate control and reproducibility while allowing both swelling of the tablet to effect gastric retention and gradual disintegration of the tablet to clear the tablet from the gastrointestinal tract after release of the drug has occurred. U.S. Pat. No. 6,340,475 highlights unit oral dosage forms of actives developed by incorporating them into polymeric matrices comprised of hydrophilic polymers that swell upon imbibing water to a size that is large enough to promote retention of the dosage form in the stomach during the fed mode. The polymeric matrix is formed of a polymer selected from the group consisting of poly (ethylene oxide), cellulose, crosslinked polyacrylic acids, xanthan gum and alkyl-substituted celluloses like hydroxymethyl-cellulose, hydroxyethyl-cellulose, hydroxypropyl-cellulose, hydroxypropylmethyl-cellulose and carboxymethyl-cellulose.
Further, gastroretentive systems based on gums have also been developed by some researchers. U.S. Pat. No. 6,635,280 discloses controlled release oral dosage form for highly water soluble drugs comprising one or more polymers forming a solid polymeric matrix which swells upon imbibition of water to a size that is large enough to promote retention of the dosage form in the stomach during the fed mode. Herein the said polymeric matrix is formed of a polymer selected from the group consisting of poly(ethylene oxide), cellulose, alkyl-substituted celluloses, crosslinked polyacrylic acids, and xanthan gum. EP Pat. No. 1745775B1 discloses gastroretentive formulation comprising an active substance granulated with a mixture of a weak gelling agent, a strong gelling agent and a gas generating agent. Herein the strong gelling agent is selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose with the exclusion of low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, guar gum, carrageenan gum, locust bean gum, sodium alginate, agar-agar, gelatin, modified starches, co-polymers of carboxyvinyl polymers, co-polymer of acrylates, co-polymers of oxyethylene and oxypropylene and mixtures thereof. U.S. Patent Application 20040219186A1 provides expandable gastric retention device comprising a gel formed from a polysaccharide, based on xanthan gum or locust bean gum or a combination thereof. U.S. Patent Application 20060177497A1 discloses gellan gum based oral controlled release dosage forms as a platform technology for gastric retention. The dosage form further comprises hydrophilic polymers such as guar gum, hydroxypropyl methylcellulose, carboxymethyl cellulose sodium salt, xanthan gum.
Most of the prior research work thus teaches use of expensive polymers like poly (ethylene oxide) for swelling or Carbopol® for mucoadhesion to develop swelling or mucoadhesive gastroretentive drug delivery systems that delay transit of the dosage form through gastrointestinal tract. A few other researchers describe use of gums of natural origin like locust bean gum; these however tend to have weaker gel strengths than required for gastroretention. Poly (ethylene oxide) is thus the major excipient employed in swelling type of gastroretentive formulations due to its excellent swelling properties. However, poly (ethylene oxide) tends to undergo oxidation with concomitant drop in viscosity which alters its performance. Moreover, poly (ethylene oxide) is very expensive and is a hygroscopic and sticky material requiring special handling precautions and cleaning methodologies. Thus there exists a need to identify excipients for development of a dosage form having delayed transit through gastrointestinal tract which are stable, easy to handle and cost effective. The present invention discloses use of fenugreek fibers for delaying the transit of a dosage form in gastrointestinal tract.
EP1697050 teaches the process of obtaining Fenugreek fibers having a ratio of insoluble to soluble fibers of greater than 0.8, preferably greater than 1.2, more preferably between about 1.2-3, having a viscosity >10,000 cps at 2% w/v and protein content of not more than 10% preferably not more than 8%. This patent also enlists various properties and applications of these fibers having a ratio of insoluble to soluble dietary fibers of greater than 1. Although many pharmaceutical applications of fenugreek fibers are disclosed in this application, it does not teach application of fenugreek fibers for making of delayed transit compositions.
The present inventors have surprisingly found that fenugreek fibers due to its excellent swelling property can be employed for the preparation of delayed transit compositions such as gastroretentive dosage forms. The use of fibers from fenugreek is cost-effective and shows hydration and swelling comparable to those produced by the polymers generally used for providing gastroretentive drug delivery systems. Further fenugreek fibers are stable, possess sufficient gel strength and do not undergo any oxidation thereby maintaining its performance over a period of time. Moreover, it was surprisingly found that the fenugreek fibers also have mucoadhesive properties, potentiating the possibility of gastric retention. Thus this single excipient may provide gastroretention by both the mechanisms of swelling and mucoadhesion, which can be used to provide delivery systems that perform better than the ones employing traditionally used excipients such as polyethylene oxide or Carbopol® or providing gastroretention by a single mechanism that can in some instances lead to failure of the system.